Age-related osteoporotic fractures are largely due to an increased propensity to fall and an increase in bone fragility due to a reduction in bone strength with aging. Several factors contribute to bone strength including bone mineral density (BMD), bone structure, and bone quality, all of which have phenotypes that are highly heritable. During the tenure of the current award we have identified several highly promising chromosomal regions that contain genes that influence peak bone strength in white and black American men and women and in rats. The goal of this application is to further define QTL that are linked to phenotypes of peak bone strength, identify which QTL are sex-specific, and to identify genes that underlie bone fragility using the combined positional cloning/candidate gene approach. It is expected that these proposed studies will greatly contribute to our understanding of the reasons for the higher risk of osteoporotic fracture in women than men and in American whites than blacks. Furthermore, identification of these genes may: 1) lead to molecular tests that predict the risk of osteoporosis, thereby allowing the early institution of preventive measures;2) provide insight into the basic skeletal biology that underlies bone fragility and the predisposition to fracture;and 3) identify molecular targets for the development of therapeutic agents aimed at increasing bone strength.